Regulation of symmetric and asymmetric cell division during brain development

大脑发育过程中对称和不对称细胞分裂的调节

基本信息

批准号：
9888448
负责人：
QIANG LU
金额：
$ 37.19万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888448
关键词：
Adult Amino Acid Sequence Behavioral Binding Biochemical Biological Biological Assay Brain Brain Diseases Caenorhabditis elegans Cell Differentiation process Cell division Cells Cerebral cortex Complex Cues Cytokinesis Data Development Developmental Brain Malformation Diagnostic Drosophila genus Electroporation Embryo Ensure Ephrins Equilibrium Event G-Protein Signaling Pathway G-substrate GTP-Binding Protein Regulators GTP-Binding Proteins Genes Genetic Goals Homologous Gene Human Invertebrates Kinesin Knowledge Lead Link Logic Maintenance Malignant neoplasm of brain Mammals Maps Mediating Mitotic Nervous system structure Neuronal Differentiation Neurons Output Pathologic Process Protein Dynamics Proteins RGS Proteins RGS3 gene Regulation Role Shapes Signal Pathway Signal Transduction Signaling Protein Work base brain malformation cell fate specification cell type daughter cell gain of function genetic approach imaging study in utero insight live cell imaging loss of function mutant nerve stem cell neurogenesis novel novel therapeutic intervention progenitor public health relevance recruit relating to nervous system self-renewal stem stem cells tool tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Neural progenitor cells maintain a tight control of the balance between self-renewal and differentiation in the developing and adult brains and can respond to environmental cues to either switch on more proliferation or produce more differentiated cells. Such a homeostatic control is not only important for normal development but also critical for proper functioning of the brain. The long-term goal of our study is to understand how self- renewal and differentiation are regulated during brain development and to apply the obtained knowledge for developing better diagnostic tools and novel therapeutic approaches for treating developmental brain disorders and brain cancers. This application proposes to investigate a novel protein interaction network that is crucial for controlling symmetric (self-renewal) versus asymmetric (differentiation) cell division in neural progenitor cells. In our previous studies, we have demonstrated, using combined cellular, embryological, and genetic approaches, that the regulator of G protein signaling (RGS)-mediated ephrin-B reverse signaling pathway is essential for maintaining the neural progenitor cell state in the embryonic cerebral cortex and that the Ga subunit signaling pathway is important for activating neuronal differentiation. We have identified a mitotic kinesin that can interact with and recruit the ephrin B/RGS proteins into the midbody of dividing neural progenitor cells, suggesting that the role of the ephrin-B/RGS pathway in neural progenitor cell regulation is linked to cytokinesis, the final stage of cell division. In addition, we have recently identified several interacting proteins of th active Ga subunits and found that these proteins, similar to Gα subunit, could activate neurogenesis. We thus propose to further characterize the biochemical interaction of the ephrin-B/RGS/mitotic kinesin and Ga subunit interaction network and examine the potential function of these networks in shaping neural progenitor cells' decision to either divide symmetrically or asymmetrically. We anticipate that the data obtained from this study will ultimately help understand what and how molecular interactions in neural progenitor cells guides the balance between self-renewal and differentiation and how dysregulation in these networks may lead to certain developmental brain disorders or tumorigenesis.

描述（由适用提供）：神经祖细胞在发育和成人大脑中自我更新和分化之间的平衡保持严格控制，并且可以响应环境线索，以使要么开启更多的增殖或产生更多分化的细胞。这种体内平衡控制不仅对正常发育很重要，而且对于大脑的正常功能至关重要。我们研究的长期目标是了解如何在大脑发育过程中调节自我更新和分化，并应用获得的知识来开发更好的诊断工具以及用于治疗发育性脑部疾病和大脑癌的新型治疗方法。这项应用提案要研究一种新型蛋白质相互作用网络，该网络对于控制对称（自我更新）与神经祖细胞中的不对称（分化）细胞分裂至关重要。在我们先前的研究中，我们使用结合的细胞，胚胎学和遗传方法证明，G蛋白信号传导（RGS）介导的Ephrin-B逆向信号通路对于维持神经元祖细胞态在胚胎脑cortex中维持神经元祖细胞状态至关重要，而GA亚基corterectex and ga subunit信号路径则具有重要的neuronynal neurony neurony neurony。我们已经确定了可以与Ephrin相互作用并募集的有丝分裂驱动器 B/RGS蛋白进入分裂神经祖细胞的中体，这表明Ephrin-B/RGS途径在神经祖细胞调节中的作用与细胞分裂的最后阶段有关。此外，我们最近已经确定了TH活性GA亚基的几种相互作用的蛋白质，发现这些蛋白（类似于Gα亚基）可以激活神经发生。因此，我们建议进一步表征ephrin-b/rgs/RGS/有丝分裂动力蛋白和GA亚基相互作用网络的生物化学相互作用，并检查这些网络在塑造神经元祖细胞对对称或不对称分裂的决定中的潜在功能。我们预计，从这项研究中获得的数据最终将有助于了解神经祖细胞中的分子相互作用以及如何指导自我更新和分化之间的平衡以及这些网络中的失调如何导致某些发育性脑部疾病或肿瘤衰变。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

KIF20A/MKLP2 regulates the division modes of neural progenitor cells during cortical development.

DOI：
10.1038/s41467-018-05152-1
发表时间：
2018-07-13
期刊：
Nature communications
影响因子：
16.6
作者：
Geng A;Qiu R;Murai K;Liu J;Wu X;Zhang H;Farhoodi H;Duong N;Jiang M;Yee JK;Tsark W;Lu Q
通讯作者：
Lu Q

Depletion of kinesin motor KIF20A to target cell fate control suppresses medulloblastoma tumour growth.